Scientists are continually searching for ways to manipulate biological factors to improve the well-being of mankind. In the pharmaceutical industry, this effort has focused primarily on finding new drugs to combat disease. While in agriculture, research has been directed toward finding new chemicals to control both disease and infestation. A new biological agent that is highly effective in vitro must be administered safely and effectively in vivo, often decreasing its practical efficiency. Until recently, the actual mechanism of delivery has received relatively little attention.
Common traditional methods of drug delivery include ingestion and injection. In either case, an initially concentrated form of the drug is rapidly diluted in a reservoir (either in the stomach or in the bloodstream) before it reaches its target. In this reservoir, the drug is also liable to removal by metabolism, excretion, or chemical degradation (for example, in the case of biosensitive materials such as proteins). From the reservoir, the agent may access organs or tissues other than the target which, even at low levels, may cause side-effects. For these reasons, the drug usually achieves a systemic concentration within the effective therapeutic range for only a short time between periods of toxicity and ineffectiveness.
A controlled release system delivers a drug at a specific rate for a definite period of time, the release kinetics being determined by the system design rather than by environmental conditions. This eliminates several of the disadvantages inherent in traditional methods of delivery, as the controlled release design offers the capability to maintain the drug level in the desired range, localized delivery to the target (lowering the systemic drug level), and preservation of biosensitive materials. Using such a device, a drug can be delivered more safely, effectively and economically.
Many of the controlled release devices that have been developed are polymeric systems. Langer, R., "New Methods of Drug Delivery", Science, 249, 1527-1533, 1990, provides an excellent review of these systems. A brief description of systems based on three mechanisms (diffusion, chemical reaction and solvent activation) that are capable of providing a constant rate of drug release is given below.
As an example of a diffusion-based system, consider a drug initially contained in a reservoir surrounded by a nonporous polymeric membrane. The drug must diffuse across the membrane and into the body, and the rate of release is controlled by the diffusivity of the drug in the membrane and the concentration difference of the drug across the membrane. If the drug is initially suspended in the reservoir, a constant thermodynamic activity of drug in solution can be maintained until all the suspended drug has dissolved and diffused out, effecting zero order release kinetics for this time period, provided the rate of solute dissolution is faster than the rate of diffusion. A variation on this concept is the matrix device, in which a drug is initially dissolved or dispersed in the polymer itself, so that the polymer serves both as a reservoir and membrane. For example, Norplant.TM. is a subdermal reservoir device that is capable of releasing contraceptive for 5 years and has been approved for use in a number of countries.
A matrix device using a polymer that can be chemically degraded by the surrounding environment is a system that is controlled by chemical reaction. The polymer can display either bulk erosion or surface erosion, the latter being more useful when maximum control over release is desired. A surface erodible polyanhydride disk containing nitrosoureas for treatment of brain cancer after surgery is currently being tested in a placebo-controlled clinical trial.
In a solvent activation system, a constant (or increasing) rate of release may be achieved using a matrix device in which polymer swelling is caused by environmental conditions. As the polymer swells, its dimensions increase, as does the diffusivity and the ratio of solubility to concentration of drug in the matrix, thereby compensating for the decrease in thermodynamic activity caused by loss of drug. Vyavahare et al., "Zero Order Release from Glassy Hydrogels. II Matrix Effects", J. Membrane Sci., 54, 205-220, 1990, have achieved zero order release kinetics for benzoic acid and theophylline from such a hydrogel system.
Sometimes it is not a constant release rate that is desired. Certain substances, such as insulin, which are normally produced by the body, would ideally be administered only as the body needs them. Fischel-Ghodsian et al., "Enzymatically Controlled Drug Delivery", Proc Natl. Acad. Sci. USA, 85, 2403-2406, 1988, have developed a system for pulsatile controlled release which is used to mimic the body's physiological process of insulin secretion. The device consists of beads on which glucose oxidase is immobilized, surrounded by a polymer matrix containing insulin. Glucose from the surroundings diffuses into the matrix to react with the glucose oxidase on the beads, forming gluconic acid as a product. As gluconic acid diffuses back out through the matrix, the pH in the matrix decreases. The decrease in pH lowers the solubility of insulin in the matrix, forcing the release of insulin. The resulting decrease in glucose level (as a result of increased glucose metabolism) is detected by the controlled release device, and insulin secretion ceases.
It is evident that a controlled release device using a porous hollow fiber has advantages over the conventional polymeric membrane devices. By careful selection of the solvent/solute/membrane system, enormous flexibility in the rate of release of a selected agent can be achieved, and the porous hollow fiber which is designed to be a highly efficient mass transfer device can be used as a rate controlling device.